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Titolo:
Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria
Autore:
Font, M; Feliubadalo, L; Estivill, X; Nunes, V; Golomb, E; Kreiss, Y; Pras, E; Bisceglia, L; dAdamo, AP; Zelante, L; Gasparini, P; Bassi, MT; George, AL; Manzoni, M; Riboni, M; Ballabio, A; Borsani, G; Reig, N; Fernandez, E; Zorzano, A; Bertran, J; Palacin, M;
Indirizzi:
Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, E-08028 Barcelona, Spain Univ Barcelona Barcelona Spain E-08028 iol Mol, E-08028 Barcelona, Spain Hosp Duran I Reynals, IRO, Ctr Genet Med & Mol, E-08907 Barcelona, Spain Hosp Duran I Reynals Barcelona Spain E-08907 l, E-08907 Barcelona, Spain Hosp CSS, IRCCS, Med Genet Serv, San Giovanni Rotondo, Italy Hosp CSS SanGiovanni Rotondo Italy t Serv, San Giovanni Rotondo, Italy TIGEM, Telethon Inst Genet & Med, I-80131 Naples, Italy TIGEM Naples Italy I-80131 ethon Inst Genet & Med, I-80131 Naples, Italy Vanderbilt Univ, Dept Med, Div Med Genet, Nashville, TN 37232 USA Vanderbilt Univ Nashville TN USA 37232 Med Genet, Nashville, TN 37232 USA Vanderbilt Univ, Dept Med, Div Nephrol, Nashville, TN 37232 USA VanderbiltUniv Nashville TN USA 37232 v Nephrol, Nashville, TN 37232 USA Inst Human Genet, IL-52621 Tel Hashomer, Israel Inst Human Genet Tel Hashomer Israel IL-52621 52621 Tel Hashomer, Israel Dept Med C, IL-52621 Tel Hashomer, Israel Dept Med C Tel Hashomer IsraelIL-52621 C, IL-52621 Tel Hashomer, Israel
Titolo Testata:
HUMAN MOLECULAR GENETICS
fascicolo: 4, volume: 10, anno: 2001,
pagine: 305 - 316
SICI:
0964-6906(20010215)10:4<305:FAOMIS>2.0.ZU;2-4
Fonte:
ISI
Lingua:
ENG
Soggetto:
LYSINURIC PROTEIN INTOLERANCE; AMINO-ACID TRANSPORTER; EXPRESSION CLONING; MOLECULAR ANALYSIS; MEMBRANE-PROTEIN; SLC3A1 GENE; HEAVY-CHAIN; IDENTIFICATION; GLYCOPROTEIN; FAMILY;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
38
Recensione:
Indirizzi per estratti:
Indirizzo: Palacin, M Univ Barcelona, Fac Biol, Dept Bioquim & Biol Mol, Avenida Diagonal 645, E-08028 Barcelona, Spain Univ Barcelona Avenida Diagonal 645 Barcelona Spain E-08028 in
Citazione:
M. Font et al., "Functional analysis of mutations in SLC7A9, and genotype-phenotype correlation in non-Type I cystinuria", HUM MOL GEN, 10(4), 2001, pp. 305-316

Abstract

Cystinuria (OMIM 220100) is a common recessive disorder of renal reabsorption of cystine and dibasic amino acids that results in nephrolithiasis of cystine, Mutations in SLC3A1, which encodes rBAT, cause Type I cystinuria, and mutations in SLC7A9, which encodes a putative subunit of rBAT (b(o,+)AT), cause non-Type I cystinuria, Here we describe the genomic structure of SLC7A9 (13 exons) and 28 new mutations in this gene that, together with the seven previously reported, explain 79% of the alleles in 61 non-Type I cystinuria patients, These data demonstrate that SLC7A9 is the main non-Type I cystinuria gene. Mutations G105R, V170M, A182T and R333W are the most frequent SLC7A9 missense mutations found, Among heterozygotes carrying these mutations, A182T heterozygotes showed the lowest urinary excretion values of cystine and dibasic amino acids, Functional analysis of mutation A182T after co-expression with rBAT in HeLa cells revealed significant residual transport activity, In contrast, mutations G105R, V170M and R333W are associated to a complete or almost complete loss of transport activity, leading to a more severe urinary phenotype in heterozygotes. SLC7A9 mutations located in the putative transmembrane domains of b(o,+)AT and affecting conserved aminoacid residues with a small side chain generate a severe phenotype, while mutations in nonconserved residues give rise to a mild phenotype, These dataprovide the first genotype-phenotype correlation in non-Type I cystinuria,and show that a mild urinary phenotype in heterozygotes may associate withmutations with significant residual transport activity.

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Documento generato il 05/12/20 alle ore 20:02:55